1. Technical Field
This invention relates to the diagnosis and treatment of a subset of individuals afflicted with an autoimmune disease, especially rheumatoid arthritis, using a V.alpha.12.1 T cell receptor-specific-reagent. Expression of the V.alpha.12.1 gene product on CD8.sup.+ T lymphocytes is elevated in a subset of rheumatoid arthritis patients when compared to the expression of V.alpha.12.1 on CD8.sup.+ lymphocytes of normal, healthy subjects that do not have the immune abnormality, thereby enabling the diagnosis and treatment of this subset of patients.
A higher level of assurance in the diagnosis of rheumatoid arthritis by V.alpha.12.1 expansion can be made by determining that the expansion is clonal or oligoclonal and that the expansion correlates with the occurrence of the HLA-DQw2 allele in V.alpha.12.1-elevated individuals.
2. Background Art
T cell precursors migrate from the bone marrow to the thymus where thymocytes begin to mature and express the T cell receptor for antigen. Through positive and negative selection, CD4.sup.+ T cells generally become restricted to major histocompatibility complex (MHC) class II molecules and CD8.sup.+ T cells to MHC class I molecules. These CD4.sup.+ or CD8.sup.+ T cells enter the periphery, where, after encountering antigen, they might be induced to become effector cells or long-lived memory cells.
The recognition of antigen and self-MHC is largely carried out by clonotypic .alpha..beta. T-cell receptors (TCR), present on the surface of T-lymphocytes in association with the CD3 complex. Like the immunoglobulins, TCR .alpha. and .beta. chains are assembled by somatic recombination of discontinuous germline gene segments during development. The generation of a highly diverse repertoire of human .alpha..beta. TCRs is accomplished by the recombination of a single V gene segment (selected from a pool of approximately 100 V.alpha.s and 80 V.beta.s) to an individual J gene segment (out of approximately 100 J.alpha.s and 13 J.beta.s). Template-independent nucleotide (N-segment) insertions at the junctions, D.beta. usage, and the imprecise joining of the germline gene segments further increase TCR diversity. Lai et al, Adv. Immunol, 46:1 (1989); Davis et al, Nature, 334:395 (1988). A dominant usage of certain V.beta. gene families in normal human peripheral T cells has been demonstrated. Choi et al, Proc. Natl. Acad. Sci. USA, 86:8941 (1989). A differential usage of specific .alpha./.beta. genes between CD4.sup.+ and CD8.sup.+ peripheral T lymphocytes has also been found. Kisielow et al, Nature, 333:742 (1988).
In autoimmune diseases, T cells are believed to act as causative agents that incorrectly recognize the host body as foreign. In the autoimmune disease rheumatoid arthritis (RA), the local site of tissue injury is the joint. Joint pathology, characterized by inflammation and joint destruction, is the result of a complex interaction of cellular elements (inflammatory cells, immunocompetent cells and synovial lining cells) and their secreted products (Zvaifler, Am. J. Med., 75:3 (1983)). The synovial tissue (pannus) in RA has the appearance of a hypercellular lymphoid organ in which the predominant lymphocytes are T cells, which make up 80% of the synovial tissue lymphocytes (Bankhurst et al, Arth. Rheum., 19:555 (1976); Kurosaka, J. Exp. Med., 158:1191 (1983)). In addition to the preponderance of T cells in the synovial pannus and an increased number of these T cells being activated in vivo, evidence for defects in T cell function and proportions have been described. Importantly, therapeutic measures that alter T cell function, such as total nodal lymphoid irradiation, significantly improve the clinical disease state but are associated with marked toxicity (Kotzin et al, N. Engl. J. Med., 305:969 (1981)).
The relative risk of RA is high in individuals who inherit certain major histocompatibility complex genes. HLA DR4 and HLA DR1, for example, are present in more than 90% of adult rheumatoid arthritis patients. While the molecular basis for this genetic predisposition is unknown, because the major function of the MHC is to present processed antigens to T lymphocytes, it has been hypothesized that an environmental antigen or infection initiates an MHC-restricted immune response mediated at least initially by T cells in RA.
For many of these reasons, scientific investigators searching for the causative agent of rheumatoid arthritis have postulated that immune dysregulation associated with the disease may be associated with clonally expanded T cells detectable as a skewing of the peripheral .alpha..beta. T cell antigen receptor repertoire. U.S. Pat. No. 4,886,743, for example, describes methods for diagnosing autoimmune diseases, including rheumatoid arthritis, based upon an expansion of V .beta. gene usage in the total population of T lymphocytes in RA patients. PCT International Publication No. 90/06758, which broadly covers monoclonal antibodies reactive with epitopes on the T cell antigen receptor that can be used in the diagnosis and treatment of many immune-related diseases, associates rheumatoid arthritis with an increased percentage of T cells which express V.delta.1, V.beta.3, V.beta.9, or V.beta.10 T cell receptor variable regions in a patient sample. Methods of diagnosing and treating RA patients with monoclonal antibodies specific for these gene products are described.
Despite the foregoing discoveries, investigators in the field of autoimmune disease pathology continue to seek correlations between the T cell antigen receptor and this chronic disease that could form the basis for future diagnostic and therapeutic modalities.
It is therefore an object of the present invention to provide a strong correlation between a variable region of the alpha chain of the T cell antigen receptor and rheumatoid arthritis.
Another object of the invention is to provide diagnostic methods and compositions for diagnosing and monitoring the progression of rheumatoid arthritis in a distinct subpopulation of RA patients.
A still further object of the invention is to provide therapeutic methods and compositions for treating a distinct subpopulation of individuals with RA.